Organ transplantation and surgical resection have been used to replace or remove diseased non-functional myocardial tissue. Recently fetal cellular transplantation has been used to improve neurological deficiencies found in Parkinson's disease (1). Normal myoblasts have been transplanted into the skeletal muscle of patients with Ducherne muscular dystrophy (2). The transplanted myoblasts expressed dystrophin. Fetal ventricular cardiomyocytes and skeletal myoblasts have been transplanted into normal myocardium by Loren Field (3, 4) U.S. Pat. No. 5,602,301). In these references, the cells were transplanted into the middle and thickest layer of the heart, composed of cardiac muscle, which has an excellent blood supply. The transplanted atrial tumor cells formed intercalated disc junctions with the host cardiomyocytes. Myocardial function measurements were not done. Since fetal ventricular cardiomyocytes and atrial tumor cells were successfully transplanted into the myocardium, it was assumed that adult ventricular cardiomyocytes could also be successfully transplanted. However, no evidence is provided that such transplantation would be successful in a damaged heart. We have shown that transplanted cells do not survive in necrosed myocardium because of the inflammatory response (Submitted to Circulation Research, not yet published). In addition to not demonstrating cell transplantation into damaged myocardium, Field does not teach the transplantation of cells into scar tissue.
Different from myocardial tissue, scar tissue in the heart has no cardiac muscle cells and is composed on connective tissue cells, such as fibroblasts, and non-cellular components, such as collagen and fibronectin. The scar tissue is formed after necrosing the ventricular wall of the heart. The mature scar tissue is though to be an inert tissue having a limited blood supply. Accordingly, from the prior art, it is not expected that cultured cells could be successfully transplanted into mature scar tissue.
Scar tissue is much thinner than normal myocardium. In accordance with the method taught by Field in U.S. Pat. No. 5,602,301, cellular grafts are introduced into the myocardium by injection. However, such method, if applied to the much thinner scar tissue, would result in a ballooning of such tissue and an accompanying increase in pressure within such area. In the result, the transplanted cellular material would leak from the puncture point of the injection needle upon withdrawal. Accordingly, the efficiency of such transplant procedure would be reduced.
Thus, there is a need to develop cellular allo- and autotransplantation technology in the scar tissue of the diseased myocardium to improve contractile function, to minimize myocardial remodeling, to stimulate angiogenesis, to deliver gene therapy, to rebuild the heart, and to salvage damaged cardiomyocytes. The present invention addresses these needs.